KR19990045744A - Amino substituted pyrimidines and triazines - Google Patents

Abstract

The present invention relates to pyrimidines and triazines of the general formula (I) having an antagonism against the CRF receptor, pharmaceutical compositions containing these compounds as active ingredients and an effective amount of a compound of the general formula (I) It relates to a method for treating diseases associated with hypersecretion of CRF such as anxiety and drug abuse.

In the above formula,

R represents C _1-6 alkyl, amino, mono- or diC _1-6 alkylamino;

R ¹ represents hydrogen, C _1-6 alkyl, C _3-6 alkenyl, hydroxyC _1-6 alkyl or C _1-6 alkyloxyC _1-6 alkyl;

R ² is C _1-6 alkyl, mono- or diC _3-6 cycloalkylmethyl, phenylmethyl, substituted phenylmethyl, C _1-6 alkyloxyC _1-6 alkyl, hydroxyC _1-6 alkyl, C _1-6 alkyloxycarbonylC _1-6 alkyl or C _3-6 alkenyl;

R ¹ and R ² together with the nitrogen atom to which they are attached may form a pyrrolidinyl, morpholinyl or piperidinyl group;

X represents N or CR ³ ;

R ³ represents hydrogen or C _1-6 alkyl;

R ⁴ represents phenyl or substituted phenyl;

A is -C (= O)-, Or -CR ⁷ R ^8- , wherein R ⁵ and R ⁶ each independently represent hydrogen or C _1-4 alkyl, R ⁷ represents hydrogen or OH, R ⁸ is hydrogen or C _1-6 Alkyl.

Description

Amino substituted pyrimidines and triazines

The first adrenal cortical hormone-releasing factor (CRF) was isolated from the hypothalamus of sheep and was identified as a 41-amino acid peptide (Vale et al., Science 213: 1394-1397, 1981). Thereafter, human and rat CRF sequences were isolated and identified as identical, but 7 CR out of 41 amino acid residues differed from positive CRF (see Rivier et al., Proc. Natl. Acad. Sci. USA 80: 4851). , 1983; Shibahara et al., EMBO J. 2: 775, 1983). CRF has been found to significantly alter endocrine, nervous and immune system functions. CRF is a major physiological modulator of normal and stress-release of pro-opiomelanocortin ("POMC")-derived peptides from adrenal cortex hormone ("ACTH"), β-endodorphine, and other anterior pituitary (Vale et al., Science 213: 1394-1397, 1981). In short, CRF can be expressed in the brain (DeSouza et al., Science 221: 1449-1451, 1984), the pituitary gland (DeSouza et al., Methods Enzymol. 124: 560, 1986; Wynn et al., Biochem. Comm. 110: 602-608, 1983), adrenal gland (Udelsman et al., Nature 319: 147-150, 1986) and spleen (Webster, EL, and EB DeSouza, Endocrinology 122: 609-617, 1988). It is thought to initiate its biological effect by binding to plasma membrane receptors found to be distributed over. CRF receptors couple with GTP-binding proteins (Perrin et al., Endocrinology 118: 1171-1179, 1986) that mediate the increased intracellular production of cAMP induced by CRF (Bilezikjian, LM, and WW Vale, Endocrinology 113: 657-662, 1983).

In addition to promoting ACTH and POMC production, CRF is also believed to cooperate with a number of endocrine autonomous and behavioral responses to stress and can be included in the pathophysiology of emotional disorders. CRF is also believed to be a major mediator in communication between the immune system, central nervous system, endocrine system and cardiovascular system (Crofford et al., J. Clin. Invest. 90: 2555-2564, 1992; Sapolsky et al. , Science 238: 522-524, 1987; Tilders et al., Regul.Peptides 5: 77-84, 1982). Overall, CRF is one of the central nervous system neurotransmitters and has been shown to play a major role in integrating the body's overall response to stress.

Direct infusion of CRF into the brain induces the same behavioral, physiological and endocrine responses observed in animals exposed to stressful environments. For example, when CRF is injected into the cerebral ventricle, behavior becomes active (Sutton et al., Nature 297: 331, 1982), activates brain waves for a long time (Ehlers et al., Brain Res. 2). / 8332, 1983), stimulate the sympathetic pathway (Brown et al., Endocrinology 110: 928, 1982), increase heart rate and blood pressure (Fisher et al., Endocrinology 110: 2222, 1982) ), Increase oxygen consumption (Brow et al., Life Sciences 30: 207, 1982), alter gastrointestinal motility (William et al., Am. J. Physiol. 253: G582, 1987), Inhibit food consumption (Levine, et al., Neuropharmacology 22: 337, 1983), alter sexual behavior (Sirinathsinghji et al., Nature 305: 232, 1983) and decrease immune function (see Irwin et al., Am. J. Physiol. 255: R744, 1988). In addition, clinical data suggest that CRF may be oversecreted in the brain in depression, anxiety-related disorders and anorexia nervosa (DeSouza, Ann. Reports in Med. Chem. 25: 215-223, 1990). .

Thus, clinical data suggest that CRF receptor antagonists may be novel antidepressants and / or anxiolytics that may be useful for treating neuropsychiatric diseases by oversecreting CRF. CRF receptor antagonists are described, for example, in US Pat. No. 5,063,245 describing substituted 4-thio-5-oxo-3-pyrazoline derivatives and Australian Patent No. AU-A41399 describing substituted 2-aminothiazole derivatives. / 93. WO-95 / 10506 describes N-alkyl-N-arylpyrimididiamines and derivatives thereof.

Because of the physiological importance of CRF, the development of biologically active small molecules that can antagonize the CRF receptor and have significant CRF receptor binding activity remains a major challenge. Such CRF receptor antagonists are generally useful for treating endocrine, psychiatric and neurological symptoms or diseases, including stress-related diseases.

The present invention relates to aminopyrimidines and -triazines having antagonism against the CRF receptor, pharmaceutical compositions containing these compounds as active ingredients and generally to endocrine, psychiatric and neurological symptoms or diseases, including stress-related diseases. To its use for treatment.

The present invention relates to aminopyrimidines and -triazines having the following general formula (I), their stereoisomers and pharmaceutically acceptable acid addition salts:

In the above formula,

R represents C _1-6 alkyl, amino, mono- or diC _1-6 alkylamino;

R ¹ represents hydrogen, C _1-6 alkyl, C _3-6 alkenyl, hydroxyC _1-6 alkyl or C _1-6 alkyloxyC _1-6 alkyl;

R ² is C _1-6 alkyl, mono- or diC _3-6 cycloalkylmethyl, phenylmethyl, substituted phenylmethyl, C _1-6 alkyloxyC _1-6 alkyl, hydroxyC _1-6 alkyl, C _1-6 alkyloxycarbonylC _1-6 alkyl or C _3-6 alkenyl;

R ¹ and R ² together with the nitrogen atom to which they are attached may form a pyrrolidinyl, morpholinyl or piperidinyl group;

X represents N or CR ³ ;

R ³ represents hydrogen or C _1-6 alkyl;

R ⁴ represents phenyl or substituted phenyl;

A is -C (= O)-, Or -CR ⁷ R ^8- , wherein R ⁵ and R ⁶ each independently represent hydrogen or C _1-4 alkyl, R ⁷ represents hydrogen or OH, R ⁸ is hydrogen or C _1-6 Alkyl;

Substituted phenyl is 1, 2 or 3 independently selected from the group consisting of halo, hydroxy, C _1-6 alkyloxy, benzyloxy, C _1-6 alkylthio, trifluoromethyl, C _1-6 alkyl and cyano Phenyl substituted by 3 substituents.

As used in the above definitions, the term halo means fluoro, chloro, bromo and iodo; C _1-2 alkyl means straight chain saturated hydrocarbon radical having 1 to 2 carbon atoms such as methyl and ethyl; C _2-4 alkyl means straight and branched chain saturated hydrocarbon radicals having 2 to 4 carbon atoms such as ethyl, propyl, butyl, 1-methylethyl and the like; C _1-4 alkyl is a straight and branched chain saturated hydrocarbon radical having 1 to 4 carbon atoms such as methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl and 1,1-dimethylethyl Means; C _1-6 alkyl means C _1-4 alkyl as defined above and higher homologues thereof having 5 to 6 carbon atoms such as pentyl, pentyl isomers, hexyl and hexyl isomers; C _3-6 alkenyl is for example 2-propenyl, 2-butenyl, 3-butenyl, 2-methyl-2-propenyl, 2-pentenyl, 3-pentenyl, 3,3-dimethyl- By straight and branched chain hydrocarbon radicals having 3 to 6 carbon atoms and having one double bond, such as 2-propenyl, hexenyl and the like. The carbon atom of the C _3-6 alkenyl moiety substituted on the NR ² R ³ _-nitrogen is preferably saturated. In case -NR ¹ R ² is a cyclic moiety, it is preferably bonded to a pyrimidine or triazine ring via a nitrogen atom.

Due to the nature of some substituents, compounds of formula (I) may contain one or more asymmetric centers which may be represented by the commonly used R and S nomenclature.

The compounds of the present invention are substituted amino compounds and can be used by themselves as free base or in the form of acid addition salts. Acid addition salts of the free base amino compounds of the present invention may be prepared by methods known in the art and may be formed from organic and inorganic acids. Suitable organic acids include maleic acid, fumaric acid, banjoic acid, ascorbic acid, succinic acid, methanesulfonic acid, acetic acid, oxalic acid, propionic acid, tartaric acid, salicylic acid, citric acid, gluconic acid, lactic acid, mandeline acid, cinnamic acid, aspartic acid, stearic acid , Palmitic acid, glycolic acid, glutamic acid and benzenesulfonic acid. Suitable inorganic acids are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and nitric acid.

Particular subgroups of compounds are those in which one or more substituents have the following meanings:

R is amino or C _1-4 alkyl, preferably C _1-2 alkyl;

R ¹ is hydrogen, C _1-6 alkyl or C _3-6 alkenyl, preferably C _2-4 alkyl or C _3-4 alkenyl;

R ² is C _1-6 alkyl, C _3-6 cycloalkylmethyl, hydroxyC _1-6 alkyl, C _3-6 alkenyl, C _1-6 alkyloxycarbonylC _1-6 alkyl, preferably C _2-4 alkyl, C _3-4 alkenyl, cyclopropylmethyl or hydroxyC _2-4 alkyl;

R ¹ and R ² together with the nitrogen atom to which they are attached may form a pyrrolidinyl, morpholinyl or piperidinyl group;

R ³ is hydrogen or C _1-4 alkyl, preferably C _1-2 alkyl;

A is -CO- or -CH _2- ;

R ⁴ is phenyl substituted by 2 or 3 substituents selected from the group consisting of halo, C _1-4 alkyloxy and C _1-4 alkyl, preferably 2 selected from the group consisting of methoxy and C _1-2 alkyl Or phenyl substituted by three substituents.

Other particular subgroups include those groups defined above where X is CR ³ or X is N.

Preferred compounds are X is CR ³ , R ³ is C _1-2 alkyl, R is C _1-2 alkyl, R ¹ is C _2-4 alkyl, R ² is cyclopropylmethyl, R ⁴ is 2 , 4,6-position is phenyl di- or trisubstituted by C _1-2 alkyl or methoxy, and A is -CO- or -CH _2- . Among them, compounds in which R ³ and R are methyl and R ¹ is n-propyl are particularly preferred.

Compounds of the invention can generally be prepared by reacting a pyrimidine or triazine substituted with a reactive group such as halopyrimidine or -triazine with a suitable amine:

In the above scheme, W represents a leaving group such as halo, for example a fluoro, chloro, bromo or sulfonyloxy group, for example a mesyloxy or tosyloxy group. The reaction is generally carried out in a suitable solvent, for example a protic solvent such as DMF or acetonitrile, ether, for example tetrahydrofuran. If A is a carbonyl group, it may be desirable to protect it according to methods known in the art.

Compounds of formula (I) may also be prepared by reacting ester substituted pyrimidines or triazines of formula (III) with Grignard reagent to yield the corresponding arylketo compounds of formula (Ia). Can be. Subsequently, the compound of general formula (Ia) is derivatized by second Grignard reaction to give the corresponding hydroxyalkyl derivative (Ib), which is then dehydrated to obtain an alkenyl derivative of general formula (Ic). . On the other hand, compound (I-a) can be reduced to the corresponding arylmethyl compound (I-d).

In the above scheme, group COOR ⁹ is an ester group in which R ⁹ is in particular a lower alkyl group, for example methyl or ethyl.

Dehydration reaction to compound (I-c) can be carried out by reacting compound (I-b) with methanesulfonyl chloride in the presence of a base.

Reduction to compound (I-d) is a method of hydrogenation, for example with hydrogen on Pd.

Compounds of formula (I) [compounds of formula (I-e)] in which the central ring is a triazine moiety can also be prepared by condensing thiourea (IV) with imideamide (V).

Radical R in the scheme is preferably amino and A is preferably a keto group. This reaction is generally carried out in a suitable solvent, for example dioxane, in the presence of a base such as an alkali metal alkoxide, for example potassium t-T-butoxide.

In the above and subsequent schemes, R is an amino group, and it may be desirable to protect according to the reaction situation. Compounds of formula (I) wherein R is mono- or dialkylamino can be prepared by alkylation reactions.

A compound of formula (I) wherein A is a -CR ⁸ OH-R ⁴ group, wherein the compound is represented by formula (If), is obtained by reacting Grignard with intermediate (VI) or compound (Ia) as starting material. Are manufactured. The reaction to reduce compound (If) to compound (Ig), which is a compound of formula (I) wherein A is —CR ⁸ HR ⁴ , is generally carried out using hydrogen on Pd.

Compounds of formula (I) can be interconverted by functional group transformation reactions known in the art. For example, amino or hydroxy groups can be alkaline; Or di-alkylated in the case of amino groups; The phenyl group can be halogenated and the halogenated phenyl group can be converted to the corresponding alkyloxy- or cyanophenyl group.

Stereoisomers are prepared by separating the final product of formula (I) according to methods known in the art, for example by treating with optically active acids and separating the formed diastereomeric salts by selective crystallization or column chromatography. can do. Stereoisomers can also be prepared using the stereoisomer starting materials in the reaction schemes described above and in the preparation of the intermediates described below.

Intermediates of formula (II-a), which are intermediates of formula (II) wherein W is halo, correspond to the corresponding hydroxycarboxylic esters of formula (II-b) homologues, for example POCl ₃ or It can be prepared by a suitable halogenation reaction with POBr ₃ , followed by a Grignard reaction. Hydroxy homologues can be prepared as follows:

Intermediate (VI) is prepared in a similar manner.

The carbonyl group of formula (II-a) may further be converted to the corresponding CH ₂ group by a reduction method similar to the reduction of compound (Ia) mentioned above to compound (Id), or compound (Ia) ) Can be converted to alkenyl groups in a manner similar to the conversion to compound (Ic).

The intermediate of general formula (II-c) can be prepared by the method described below for producing intermediate (III-c) having the same structure.

Intermediates of formula (III), wherein X is CR ³ , can be prepared according to the following scheme.

Intermediates of the same formula (II) can be prepared as follows:

In the above scheme, W and R ⁹ have the meanings mentioned above and M is a metal cation. Treatment of intermediate (III-i) with an amine affords compound (III-h), which is subsequently followed by SeO ₂ and metal carbonates or bicarbonates, where the metal is preferably an alkali metal, for example NaHCO ₃ or Treatment with CS ₂ CO ₃ introduces carboxyl groups. Intermediate (III-g) is esterified with alcohol, for example with SOCl ₂ , to afford the intermediate of formula (III-j).

Intermediates of formula (IV) are prepared from the corresponding keto-esters of formula (IV-a) as follows:

In the above scheme, R ¹⁰ is hydrogen or lower alkyl, for example ethyl.

The effectiveness of a compound as a CRF receptor antagonist can be determined by various test methods. Suitable CRF antagonists of the present invention can inhibit CRF specifically binding to its receptor and can antagonize the activity associated with CRF. Compounds of formula (I) are not limited to the tests described in DeSouza et al. (J. Neuroscience 7:88, 1987) and Battaglia et al. (Synapse I: 572, 1987). Can be assessed for activity as a CRF antagonist by one or more test methods commonly used for this purpose. As mentioned above, suitable CRF antagonists include compounds having affinity for the CRF receptor. CRF receptor affinity is a binding assay that measures the degree of a compound that inhibits the binding of radiolabeled CRF (eg [ ¹²⁵ I] tyrosine CRF) to a receptor (e.g., a receptor made from rat cerebral cortex). Can be determined by testing. DeSouza et al. Radioligand binding assays described in supra, 1987, provide assays to determine affinity of compounds for CRF receptors. This activity is generally calculated from the IC ₅₀ as the concentration of compound required to escape 50% of the radiolabeled ligand from the receptor and is reported as the "K _i " value calculated from the following formula:

K _i = (IC ₅₀ / (1 + L / K _D ))

In the above formula,

L is a radioligand,

K _D is the affinity of the radioligand to the receptor (Biochem. Pharmacol. 22: 3099, 1973 by Chen and Prusoff).

In addition to inhibiting CRF receptor binding, the activity of antagonizing a compound's CRF receptor can be established by the compound's ability to antagonize the activity associated with CRF. For example, CRF is known to stimulate various biochemical processes, including adenylate cyclase activity. Thus, compounds can be evaluated as CRF antagonists by their ability to antagonize the activity of CRF-induced adenylate cyclase, for example by measuring cAMP levels. Battaglia et al. From assaying the activity of CRF-induced adenylate cyclase described in supra, 1987, one can derive a test that measures the ability of a compound to antagonize CRF activity. Thus, CRF receptor antagonistic activity generally involves performing an initial binding test (as described in DeSouza (supra, 1987)) followed by a cAMP selection protocol (as described in Battaglia (supra, 1987)). Can be measured by a test technique. With regard to CRF receptor binding affinity, the CRF receptor antagonists of the invention have a K _i of less than 10 mM. In a preferred embodiment of the invention, the CRF receptor antagonist has a K _i of less than 1 mM and more preferably less than 0.25 mM (ie 250 nM).

CRF receptor antagonists of the present invention exhibit activity at the CRF receptor site and can be used as therapeutic agents for treating a wide variety of diseases or conditions, including endocrine, psychiatric and neurological diseases or conditions. More specifically, the CRF receptor antagonists of the present invention may be useful for treating physiological symptoms or diseases caused by hypersecretion of CRF. Since CRF is thought to be a central nervous system neurotransmitter that activates and coordinates endocrine, behavioral and autonomous responses to stress, the CRF receptor antagonists of the present invention can be used to treat neuropsychiatric diseases. Neuropsychiatric diseases that can be treated by the CRF receptor antagonists of the present invention include emotional disorders such as depression; Anxiety-related disorders such as cardiovascular disorders such as generalized anxiety disorder, panic disorder, obsessive compulsive disorder, abnormal aggression, unstable angina and reactive hypertension; And food intake disorders such as anorexia nervosa, bulimia and irritable bowel symptoms. CRF antagonists may also be useful for treating stroke as well as immune suppression by stress accompanying various disease states. Still other uses of CRF antagonists according to the invention include inflammatory symptoms (such as rheumatoid arthritis, uveitis, asthma, inflammatory bowel disease and GI motility), Cushing's disease, infant cramps, epilepsy, infant and adult seizures, and Treatment of various drug abuse and withdrawal (including alcoholism).

In another embodiment of the present invention, pharmaceutical compositions containing one or more CRF receptor antagonists are described. For the purpose of administration, the compounds of the present invention may be formulated in pharmaceutical compositions. The pharmaceutical composition of the invention contains a CRF receptor antagonist of the invention (ie, a compound of formula (I)) and a pharmaceutically acceptable carrier and / or diluent. The CRF receptor antagonist is present in the composition in an amount effective to treat a particular disease, ie, an amount sufficient to achieve CRF receptor antagonistic activity, preferably at an acceptable level of toxicity for the patient. Preferably, the pharmaceutical composition of the present invention may contain the CRF receptor antagonist in an amount of 0.1 mg to 250 mg, and more preferably 1 mg to 60 mg per dose, depending on the route of administration. Suitable concentrations and dosages can be readily determined by one skilled in the art.

Pharmaceutically acceptable carriers and / or diluents are well known to those skilled in the art. For compositions formulated as liquid solutions, acceptable carriers and / or diluents include saline and sterile water and optionally contain antioxidants, buffers, bacteriostatic agents and other conventional additives. The composition may be formulated as pills, capsules, granules or tablets containing diluents, dispersants, surfactants, binders and lubricants, in addition to CRF receptor antagonists. Those skilled in the art can further formulate the CRF receptor antagonist in a suitable manner in accordance with conventional practice, as described in Remington's, Pharmaceutical Sciences, Gennaro, Ed., Mack Publishing Co., Easton, USA, 1990. .

In another embodiment, the present invention provides methods for treating various symptoms or diseases, including endocrine, psychiatric and neurological symptoms or diseases. The method comprises administering a compound of the present invention to a warm blooded animal in an amount sufficient to treat such condition or disease. This method comprises systemic administration of a CRF receptor antagonist of the invention, preferably in the form of a pharmaceutical composition. As used herein, systemic administration includes oral and parenteral administration. For oral administration, suitable pharmaceutical compositions of CRF receptor antagonists include powders, granules, pills, tablets and capsules, as well as solutions, syrups, suspensions and emulsions. These compositions also contain flavorings, preservatives, suspending agents, thickening agents, emulsifiers and other pharmaceutically acceptable additives. In the case of parenteral administration, the compounds of the present invention may be prepared as aqueous injection solutions which may contain, in addition to CRF receptor antagonists, buffers, antioxidants, bacteriostatic agents and other additives commonly used in such solutions. .

As mentioned above, various disorders or diseases can be treated by administering the compounds of the present invention. In particular, the compounds of the present invention include depression, emotional disorders, panic disorders, obsessive compulsive disorder, abnormal aggressiveness, unstable angina, reactive hypertension, anorexia nervosa, bulimia, irritable bowel symptoms, stress-related immune suppression, stroke, inflammation, Cushing's disease, It may be administered to warm blooded animals to treat infant cramps, epilepsy, and various drug abuse and withdrawal symptoms.

The following examples are presented for illustrative purposes and are not intended to be limiting.

Experimental part

Example 1: Preparation of 4-amino-pyrimidine-6-carboxylic acid, ester

1a) 4-chloro-2,5-dimethylpyrimidine-6-carboxylic acid, ethyl ester (10 mmol) (compound 11 as described in J. Org. Chem., 46, p 1413-1412 (1981)) and substitutions Solution of amine (5 mL) was refluxed in acetonitrile for 4 hours, or the mixture was heated at 120 ° C., neat for 3 hours. The mixture is cooled to room temperature. The reaction mixture is then worked up by one of the following methods (1) and (2). (1) The reaction mixture is diluted with hexane, filtered and the filtrate is concentrated and the residue is purified by SiO ₂ chromatography (EtOAc / hexanes). (2) The mixture is concentrated and purified by SiO ₂ chromatography (EtOAc / hexanes). As a result, the desired 4-alkylamino-2,5-dimethylpyrimidine-6-carboxylic acid, ester was obtained. 2,5-dimethyl-4- (N-propyl-N) by carrying out the process using 2.8 g (13 mmol) of the pyrimidine ethyl ester and excess N-propyl-N-cyclopropylmethylamine as starting material. -cycle

Ropropylmethyl-amino) -pyrimidine-6-carboxylic acid, ethyl ester was obtained.

1b) A solution of 2,6-dimethyl-4-chloropyrimidine (1.7 g, 11 mmol) in 15 mL of dipropylamine is refluxed for 18 hours. The solution is cooled to room temperature and then poured into ethyl acetate / water. The organic phase is washed with water and then brine, dried (MgSO ₄ ) and then concentrated. 2.3 g of yellow oil is obtained. Proton NMR confirmed this material to be pure 2,6-dimethyl-4- (N, N-dipropyl) pyrimidine. This material is used directly in the next step.

1c) A solution of 2,4-dimethyl-6- (N, N-dipropyl) pyrimidine (1.73 g, 8.4 mmol) in 13 mL of anhydrous pyridine is treated with SeO ₂ (1.18 g, 10 mmol). The suspension is refluxed for 5 hours, cooled, diluted with 100 ml of water and filtered. The filtrate is concentrated in vacuo, diluted with water and then concentrated. The residue is dissolved in a sufficient amount of saturated NaHCO ₃ to give a mixture of pH8 and washed twice with ethyl acetate. The aqueous phase is concentrated to dryness. This solid residue is suspended in 20 ml of anhydrous methanol and 2 ml of SOCl ₂ . The suspension is stirred at 22 ° C. for 20 hours. The mixture is diluted with water, neutralized with NaHCO ₃ and then extracted with EtOAc. The organic phase is washed with brine, dried (MgSO ₄ ) and then concentrated. The residue is purified by flash chromatography (0-40% EtOAc / hexanes) to afford 2-methyl-4- (N, N-dipropyl) -pyrimidine-6-carboxylic acid, methyl ester. This material, having a melting point of 45 to 46 DEG C, is solidified upon standing.

1d) A solution of 2,6-dimethyl-4-chloropyrimidine (4.4 g, 30.9 mmol) and N-propyl-N-cyclopropylmethylamine (7.2 g, 64 mmol) is refluxed for 10 hours. The solution is cooled to room temperature and then poured into ethyl acetate / water. The organic phase is washed with water and then brine, dried (MgSO ₄ ) and then concentrated. 6.4 g of a yellow oil are obtained. Proton NMR confirmed this material to be 2,6-dimethyl-4- (N-propyl-N-cyclopropylmethylamino) pyrimidine. This material is used directly in the next step.

1e) A solution of 2,6-dimethyl-4- (N-propyl-N-cyclopropylmethylamino) pyrimidine (2.2 g, 10 mmol) in 15 mL of anhydrous pyridine was dissolved in SeO ₂ (1.4 g, 12.5 mmol). To be processed. The suspension is refluxed for 5 hours, cooled, diluted with 100 ml of water and filtered. The filtrate is concentrated in vacuo, diluted with water and then concentrated. The residue is partitioned between ethyl acetate and a solution of 1.65 g of Cs ₂ CO ₃ in 100 ml of water. The aqueous phase is washed with ether, concentrated to dryness. After drying under high vacuum overnight, the residue is suspended in 60 ml of DMF, concentrated, then the residue is resuspended and concentrated again. The residue is suspended in 60 ml of DMF and 2 ml of iodomethane are added. The suspension is stirred at 22 ° C. for 5 hours. The mixture is diluted with water and extracted with EtOAc. The organic phase is washed with brine, dried (MgSO ₄ ) and then concentrated. The residue was purified by flash chromatography (10-40% EtOAc / hexanes) to give 2-methyl-4- (N-propyl-N-cyclopropylmethylamino) -pyrimidine-6-carboxylic acid, methyl ester (350 mg ). TLC (50% EtOAc / hexanes, Rf = 0.4).

1f) Ethyl ethoxalyl butyrate is prepared in a similar manner to methyl ethoxalyl butyrate (Org. Syn. Coll. Vol. 2, 272-273). This compound was prepared using 4-hydroxy-2-methyl- using the method described by S. Hecht, et al. (J. Org. Chem., 46, 1413-1423 (1981)). 5-ethyl-pyrimidine-6-carboxylic acid, ethyl ester, and then 4-chloro-2-methyl-5-ethyl-pyrimidine-6-carboxylic acid, ethyl ester.

Example 2: Preparation of 6-phenylketopyrimidine A

A solution of a suitable 4- (N-alkylamino) pyrimidine-6-carboxylic acid ester derivative (0.4 mmol) in 5 mL of THF (under a nitrogen atmosphere) is cooled to -78 ° C and THF (0.8 mL) with gentle stirring. Treated with 1M solution of substituted Grignard reagent. After 1 hour, the solution is slowly warmed to room temperature. The reaction mixture is poured into water and extracted with EtOAc. The organic extract is washed with brine, dried (MgSO ₄ ) and then concentrated. The residue is purified by SiO ₂ chromatography (EtOAc / hexanes) to afford 4- (N-alkylamino) -6- (substituted phenylketo) -pyrimidine derivatives.

Example 3: Preparation of 6-phenylketopyrimidine B

3a) A solution of 2,5-dimethyl-4-chloro-pyrimidine-6-carboxylic acid, ethyl ester (3.2 g, 30 mmol) in 70 mL THF was cooled to -78 ° C and a 1M solution of mesitylene magnesium bromide 50 ml is added dropwise. This solution is slowly warmed to room temperature. The reaction mixture is poured into 6 g of NH ₄ Cl solution in 300 ml of water and extracted with CHCl ₃ . The organic phase is washed with brine, dried and concentrated. The residue was purified by SiO ₂ chromatography (20% EtOAc / hexanes) to give 3.2 g of 2,5-dimethyl-4-chloro-6- (2 ', 4', 6'-trimethylphenylketo) -pyrimidine To obtain.

3b) A solution of a suitable 2,5-dimethyl-4-chloro-6- (2 ', 4', 6'-trimethylphenylketo) pyrimidine (100 mg, 0.3 mmol) in 1 ml of acetonitrile is gently It is refluxed with 1.5 mmol of substituted amine with stirring. After 4 hours, the solution is cooled to room temperature. The reaction mixture is poured into water and extracted with EtOAc. The organic extract is washed with brine, dried (MgSO ₄ ) and then concentrated. The residue is purified by SiO ₂ chromatography (EtOAc / hexanes) to afford 4- (N-alkylamino) -6- (substituted phenylketo) -pyrimidine derivatives.

Example 4: Preparation of 6-phenylketopyrimidine C

4a) To a solution of mesitylene (35 mL, 0.251 mol) and ethyl oxalyl chloride (36.4 g, 0.266 mol) in dichloromethane (150 mL) was added dropwise aluminum chloride (35.2 g, 0.265 mol) at 0 ° C. The resulting red solution is stirred at 0 ° C. for 1 hour and then at room temperature overnight. The reaction is carefully quenched with ice while the flask is cooled in an ice water bath. The mixture is extracted with ethyl acetate (500 + 200 mL). The extract is washed with brine, saturated NaHCO ₃ and brine, dried over MgSO ₄ , filtered and concentrated in vacuo to give mesitylglyoxylate as a yellow solid (34 g, 60%).

¹ H NMR δ 1.40 (t, 3H), 2.28 (s, 6H), 2.33 (s, 3H), 4.40 (q, 2H), 6.90 (s, 2H).

The aqueous NaHCO ₃ phase is acidified with concentrated HCl to pH 3 and extracted with ethyl acetate (2 × 200 mL). The extract is washed with brine, dried over MgSO ₄ , filtered and concentrated in vacuo to give ethyl mesitylglyoxylic acid as a yellow oil (19.5 g, 40%).

¹ H NMR δ 2.21 (s, 6H), 2.34 (s, 3H), 6.65 (brs, 1H), 6.93 (s, 2H).

4b) Mesitylglyoxylic acid (1.92 g, 10 mmol) is dissolved in dichloromethane (30 mL). Oxalyl chloride (2 mL, 23 mmol) is added followed by one drop of DMF. The mixture is stirred at room temperature for 1 hour. Excess oxalyl chloride and solvent are removed in vacuo. Acid chloride is dissolved in acetone (5 mL) and added to a solution of sodium thiocyanate (1.0 g, 12 mmol) in acetone (30 mL) at 0 ° C. with vigorous stirring. After 10 minutes n-propylcyclopropanemethylamine (1.13 g, 10 mmol) is added and the yellow suspension is stirred at 0 ° C. for 30 minutes. Sodium carbonate (1.3 g, 12.5 mmol) and methyl iodide (2.84 g, 20 mmol) are added and the mixture is stirred at rt overnight. The suspension is partitioned into ethyl acetate-water (200-50 mL) and the organic layer is washed with brine, dried over MgSO ₄ , filtered and evaporated in vacuo to give a yellow oil which is chromatographed (1: 3). To 1: 1 ethyl acetate-hexane). S-methyl-N-acylthiourea is obtained as a yellow oil (1.5 g, 42%).

¹ H NMR δ 0.15-1.75 (m, 10H), 2.27 (s, 6H), 2.43 (s, 3H), 3.39 (d, 2H), 3.51 (m, 2H), 6.82 (s, 2H).

4c) The obtained thiourea (20 mg, 0.056 mmol) is mixed with guanidine hydrochloride (50 mg, 0.53 mmol) and potassium t-butoxide (55 mg, 0.49 mmol) in dioxane (2 mL). The suspension is heated to reflux for 3 hours. The product is purified by preparative TLC using 1: 3 ethyl acetate-hexanes. 7 mg of colorless oil is obtained.

¹ H NMR δ 0.30 (m, 2H), 0.62 (m, 2H), 0.96 (t, 3H), 1.05 (m, 1H), 1.65 (m, 2H), 2.24 (s, 6H), 2.30 (s, 3H), 3.25 (d, 2H), 3.40 (t, 3H), 6.87 (s, 2H), 8.75 (brs, 2H).

Example 5

6- (cyclopropylmethyl) [propylamino] (2,5-dimethyl-4-pyrimidinyl) (2,4,6-trimethoxyphenyl) methanone (100 mg, in 1 mL CH ₂ Cl ₂ ) 0.24 mmol) is cooled in an ice bath, 1.2 ml of 2M trimethylaluminum is added dropwise, followed by the dropwise addition of trimethylsilyltriplate (0.48 ml, 2.4 mmol). The solution is stirred at 5 ° C. for 1 hour and then at room temperature for 3 hours. The reaction mixture is poured into 5% NaHCO ₃ and extracted with ethyl acetate, then the organic phase is dried (MgSO ₄ ) and concentrated. Preparative TLC (50% EtOAc / hexanes) was carried out to give gem-dimethyl derivative and 6-[(2,4,6-trimethoxyphenyl) 2-2-ethenyl] -2,5-dimethyl-N-propyl- N-cyclopropylmethyl-4-pyrimidinamine (30 mg) (Compound 9) is obtained.

Example 6

6a) 413 mg (1.00 mmol) of 2,5-dimethyl-4- (N-propyl-N-cyclopropylmethylamino) -6- (2 ', 4', 6 'in 50 ml of THF at -78 ° C. To a solution of -trimethyloxyphenylketo) pyrimidine 1.5 ml of 2.0 M isopropyl magnesium chloride (3.0 mmol) in THF is added. Confirm that the starting material was consumed completely by TLC (EtOAc), the solution was quenched with aqueous sodium bicarbonate solution, then warmed to room temperature, extracted with chloroform and evaporated under reduced pressure. After NMR analysis, alcohol (6-[(cyclopropylmethyl) propylamino] -2,5-dimethyl-α- (1-methylethyl) -α- (2,4,6-trimethoxyphenyl) -4- Pyrimidinmethanol is used in the next step without further purification.

6b) The alcohol is dissolved in 50 ml of chloroform. 1 ml of Et ₃ N and 0.5 ml of methanesulfonyl chloride are added. After 30 minutes at room temperature, an aqueous sodium bicarbonate solution is added. The mixture is extracted with 200 ml additional chloroform and then concentrated. After two chromatographic separations, olefin (6- [2 '-(2'',4'',6''-trimethoxyphenyl)-2'-propenyl] -2,5-dimethyl-4- (N -Propylcyclopropylmethylamino) -pyrimidine).

Example 7

2,5-dimethyl-4- (N-propyl-N-cyclopropylmethylamino) -6- (2 ', 4', 6'-trimethyloxyphenylketo) pyrimidine in 5 ml of glacial acetic acid (50 mg, 0.12 mmol) is treated with 50 mg of Pd on 10% activated carbon and shaken under 3.45 10 ⁵ Pa hydrogen for 4 hours. The mixture was filtered, concentrated and purified by preparative TLC (60% EtOAc / hexanes) to 20 mg of 2,6-dimethyl-4- (N-propyl-N-cyclopropylmethylamino) -6- (2 Obtain ', 4', 6'-trimethyloxyphenylmet-1'-yl) pyrimidine (compound 20).

A number of compounds that can be prepared according to the methods described above are listed in the table below:

Compound number R ³ R R ¹ R ² A R ^a R ^b R ^c Way 1 2 3 4 5 HCH ₃ HHCH ₃ CH ₃ CH ₃ CH ₃ CH ₃ CH ₃ (CH ₂ ) ₂ CH ₃ (CH ₂ ) ₂ CH ₃ (CH ₂ ) ₂ CH ₃ (CH ₂ ) ₂ CH ₃ (CH ₂ ) ₂ CH ₃ (CH ₂ ) ₂ CH ₃ CH ₂ -cyclopropylCH ₂ -cyclopropylCH ₂ -cyclopropylCH ₂ -cyclopropyl CH ₃ CH ₃ OCH ₃ OCH ₃ CH ₃ CH ₃ CH ₃ OCH ₃ OCH ₃ CH ₃ CH ₃ CH ₃ OCH ₃ OCH ₃ CH ₃ AAAAA

Compound number R ³ R Z A R ^a R ^b R ^c Way 2324 CH ₃ CH ₃ CH ₃ CH ₃ CH ₃ CH ₃ CH ₃ CH ₃ CH ₃ CH ₃ BB

Compound number R R ¹ R ² R ^a R ^b R ^c Way 25 NH ₂ n-propyl CH ₂ -cyclopropyl CH ₃ CH ₃ CH ₃ C

Analytical data for the compounds described in Tables 1-3 are summarized in Table 6:

Compound number R ¹ R ² Way Mass Spectrum Data [M + 1 ⁺ ] 26 (CH ₂ ) ₂ -CH ₃ c.propyl-methyl A 338

Compound number R ¹ R ² Way Mass spectral data [M + 1 ⁺ ] 2728293031 CH ₃ H (CH ₂ ) ₃ -CH ₃ CH ₃ H CH ₃ (CH ₂ ) ₅ -CH ₃ (CH ₂ ) ₃ -CH ₃ phenylmethylCH ₃ BBBBB 297353381373283

Compound number R ¹ R ² Way Mass Spectrum Data [M + 1 ⁺ ] 3233343536373839404142434445464748 (CH ₂ ) ₃ -CH ₃ HHHH 1 -methylethylHCH ₂ -CH ₃ HHHCH ₂ -CH ₂ OHHHHCH ₂ -CH ₂ OHH Phenylmethyl4-chlorophenylmethyl4- (trifluoromethyl) phenylmethylc.hexylmethyl2-methylphenylmethyl1-methylethyl3,4-dimethoxyphenylmethylCH ₂ -CH ₃ 2-chlorophenylmethyl3,4 -Dichlorophenylmethyl3,4,5-trimethoxyphenylmethylphenylmethyl2,3-dimethoxyphenylmethyl2-propenylphenylmethylCH ₂ -CH ₂ OHc.propylmethyl BBBBBBBBBBBBBBBBB 415393427365373353415325394429449403-309359357324

Compound number R ¹ R ² Way Mass Spectrum Data [M + 1 ⁺ ] 4950515253545556575859606162636465 CH ₂ -CH ₃ HHCH ₂ -CH ₃ HHHHHHHHHHHHH 2-methyl-2-propenyl (CH ₂ ) ₃ -CH ₃ 1,1-dimethylethyl (CH ₂ ) ₃ -CH ₃ 3,5-dimethoxyphenylmethyl1-methylbutyl2- (trifluoromethyl) Phenylmethyl (CH ₂ ) ₃ -CH ₃ 2-fluorophenylmethyl2-methoxyphenylmethyl2-ethoxyphenylmethyl3-methylphenylmethyl3-fluorophenylmethyl4-methylphenylmethyl4-fluorophenylmethyl4- Methoxyphenylmethyl2,6-difluorophenylmethyl BBBBBBBBBBBBBBBBB 351325325353419339427311377389403373377373377389395

Compound number R ¹ R ² Way Mass Spectrum Data [M + 1 ⁺ ] 6667686970717273747576777879808182 (CH ₂ ) ₃ -O-CH ₃ HHHHHHHHCH ₃ HCH ₃ HHHHH 3,4,5-trimethoxyphenylmethylCH ₂ -CH ₃ 1-methylethyl1-methylpropyl2-methylpropyl3-methylbutyl1,2-dimethylpropyl1,3-dimethylbutyl 3,3-dimethylbutyl (CH ₂ ) ₂ -CH ₃ (CH ₂ ) ₃ -O-CH ₂ -CH ₃ 2-propenyl3-trifluorophenylmethyl (CH ₂ ) ₄ -CH ₃ (CH ₂ ) ₃ -O-CH ₃ CH (CH ₃ ) (CH ₂ OCH ₃ ) (CH ₂ ) ₃ OCH (CH ₃ ) ₂ BBBBBBBBBBBBBBBBB 521297311325325339339353353325355323 ---- 369

Compound number R ¹ R ² Way Mass Spectrum Data [M + 1 ⁺ ] 838485868788 HHHHH (CH ₂ ) ₂ OH (CH ₂ ) ₃ OHCH (CH ₂ CH ₃ ) ₂ CH (CH ₂ OH) (CH ₂ ) ₃ CH ₃ CH (CH ₂ OH) (CH ₂ ) ₃ CH ₃ BBBBBB --339369355337 -(CH ₂ ) ₅ -( ^* )

( ^* ): R <^1> and R <^2> form together.

Example 8

Representative Compounds Having CRF Receptor Binding Activity

The compound is described in DeSouza et al. Neurosci. 7: 88-100, 1987, was evaluated for binding activity to the CRF receptor by standard radioligand binding assays generally described. Several radiolabeled CRF ligands were used in the assay to assess the binding activity of the compounds of the invention having CRF receptor subtypes. In short, binding assays include the release of radiolabeled CRF ligand from the CRF receptor.

More specifically, binding assays are performed in 1.5 ml Eppendorf tubes using about 1 × 10 ⁶ cells per tube stably infected with human CRF receptors. Test buffers with or without CRF (final concentration 1 mM), eurotensin I or unlabeled sauvagine to determine nonspecific binding to each tube (eg Dulbecco phosphate buffered saline, 10 containing about 0.1 mL of magnesium chloride, 20 μM bacitracin), 0.1 mL of [ ¹²⁵ I] tyrosine-positive CRF (final concentration ˜200 pM or approximately K _D measured by Scatchard analysis) and CRF receptor Introduce 0.1 ml of the membrane suspension of cells. The mixture is incubated at 22 ° C. for 2 hours and then centrifuged to separate bound and free spin ligands. The pellet was washed twice, the tube was cut directly above the pellet and then irradiated for radioactivity at an efficiency of about 80% in a gamma-counter. All radioligand binding data were analyzed using a non-linear least-square curve-fitting program. Binding activity corresponds to the concentration (nM) of the compound required to escape 50% of the radiolabeled ligand from the receptor. Compounds 2, 5, 8, 13, 14, 20, 28, 73, 82, 85, 86 and 87 described in Tables 1 to 5 have K _i values of ≦ 250 nM. In this test, Compound 8 was found to have the best score.

Example 9

CRF-induced adenylate cyclase activity

The compounds of the present invention can also be evaluated by various functional tests. For example, compounds of the present invention were screened for CRF induced adenylate cyclase activity. Assays for CRF induced adenylate cyclase activity can be performed by modifying methods generally described in Battaglia et al. (Synapse 1: 572, 1987) to suit whole cell assays. More specifically, the standard assay mixture may contain 0.5 ml: 2 mM L-glutamine, 20 mM HEPES and 1 mM IMBX in DMEM buffer in final volume. In the induction test, whole cells with transfected CRF receptors were plated in 24 well plates and incubated at 37 ° C. for 1 hour with varying concentrations of CRF-associated and unrelated peptides for pharmacological ranking of specific receptor subtypes. To establish it. After incubation, the medium is aspirated, the wells are rinsed once with fresh medium and the medium is aspirated. To determine the amount of intracellular cAMP, 300 μl of a solution of 20 mM aqueous hydrochloric acid and 95% ethanol is added to each well and the resulting suspension is incubated at −20 ° C. for 16-18 hours. The solution is taken out and introduced into a 1.5 ml Eppendorf tube, the wells are washed with additional 200 μl of ethanol / hydrochloric acid and then pooled with the first fraction. Samples are lyophilized and resuspended with 500 μl sodium acetate buffer. CAMP in the sample is measured using a single antibody kit. To measure the function of a compound, a single concentration of CRF or a related peptide that induces 80% of cAMP production is incubated with various concentrations of competing compounds ( ^10-2 to ^10-6 M).

Example 10

The plus-maze and defensive withdrawl paradigm are complementary to measure exploratory behavior sensitive to anxiety-promoting and anxiety-relieving effects by experimental treatment. This animal model was used to investigate the anti-anxiety and anti-stress action of the compounds of the present invention.

Elevated Plus-Maze Paradigm

This test predicts how many animals can respond to approach-avoidance situations, including bright and dark safe spaces. Both spaces are separated from the ground and consist of two mains crossing in the form of a plus sign. This type of approach-avoidance situation is a classical test method for investigating "emotions" and responsiveness and is very sensitive to deinhibition (such as calm / hypnosis) and stress-forming processes. There is no need to limit movement and allow the animal to remain free in the dark or escape with an open arm. The plus-maze device has four arms (10 x 50 cm) at an angle of 90 degrees and is located 50 cm from the floor. The two arms are blocked by a wall (40 cm high) and the two arms have no barriers (open arms). The subjects are individually placed in the center of the maze and allowed free access to four arms for 5 minutes. Observe the object through the window in the door and at the same time make the rat's position on-line display on the computer monitor. The time spent in each arm is automatically recorded by the photocell beam and the computer program. Wipe the maze with a damp cloth between each test. In this experiment, anxiety-promoting behavior is measured as a decrease in the time spent in the open arm, and the anti-stress effect is measured as a complementary increase in the time spent in the open arm.

Validity of Plus-Maze with CRF Peptides

Central administration of CRF and exposure to several experimental stressors inhibit the exploratoryness of an expensive plus maze model wrapped in anxiety. When measuring behavioral responses to social frustration, centralized administration of alpha-helix CRF (9-41) antagonists post-stress [25 μg ICV] or prestress [1 μg ICN] promotes social frustration. The effect is reversed. The anti-stress action of these CRF antagonists also reaches the central nucleus of the cerebellar tonsils after arrival of the cerebral [250 ng IC].

Rats are administered orally with test compounds 1 hour before the 5 minute test. Some groups are placed in a pool full of water just before introduction into the plus-maze (stress group), and control groups are pulled directly from the cage (non-stress group). It was observed that the average percentage of time spent in open arms was significantly reduced (about 25 to about 10%) in the non-treated animals group. Administration of Compound 2 at 0.16 or 2.5 mg / kg resulted in the percentage of time spent in the open arm returning to the same level as the untreated group within the margin of error. The same test was performed on compound 5 to obtain similar results, demonstrating that these two compounds exhibit anti-stress activity.

Defensive Retreat Paradigm

The test was carried out in an open field (106 × 92 × 77 cm) of plastic glass including a steel chamber with a cylindrical direct current electric current having a diameter of 10.2 cm and a depth of 17.1 cm. The chamber is open at one end and placed side by side with the wall of the open field so that it is vertically aligned 15.0 cm from the corner of the open field. The open end faces with the corner. The fluorescent light is illuminated from the ceiling into the open field. For testing, animals are introduced into an unfamiliar test environment by placing them in a small chamber. The test time is 5 minutes and after each test the device is wiped off with a mild acetic acid solution. Test compounds are administered orally 5 minutes before the test. Monitor animal behavior and record with video camera. The latency to escape the chamber is measured, which is defined as all four feet in the open field. The average length of time in the chamber per inlet and the number of passages made between the chamber and the open field are also measured. Anxiety relief effects are measured as a reduction in the mean time spent in a closed chamber. When oral administration of Compound 8 to rats at 0.16, 2.5 and 20 mg / kg, the mean time in the chamber decreased from about 40 seconds to about 10 to 20 seconds.

Feasibility of Defensive Retraction Using CRF Peptides

ICV injection of both alpha-helix CRF (9-41) and CRF results in changes in behavior in the defensive retreat paradigm. In particular, ICV administration of CRF to animals already familiar with the device increases both the latency from the small chamber and the average time spent in the chamber to more than 15 minutes. Similarly, the injection of CRF into the platen produces a similar change in protective retraction behavior, meaning that the interaction between CRF and noradrenaline neurons is accompanied during protective retraction behavior in rats. Conversely, ICV administration of competitive CRF receptor antagonists, alpha-helical CRF (9-14) or d-Phe CRF (12-41), reverses the effect of CRF on restraint stressors in familiar environmental conditions and is not device-friendly. The average time in the chamber and the escape latency in animals are significantly reduced.

Claims (14)

Compounds of the general formula (I), their stereoisomers and pharmaceutically acceptable acid addition salts: In the above formula, R represents C _1-6 alkyl, amino, mono- or diC _1-6 alkylamino; R ¹ represents hydrogen, C _1-6 alkyl, C _3-6 alkenyl, hydroxyC _1-6 alkyl or C _1-6 alkyloxyC _1-6 alkyl; R ² is C _1-6 alkyl, mono- or diC _3-6 cycloalkylmethyl, phenylmethyl, substituted phenylmethyl, C _1-6 alkyloxyC _1-6 alkyl, hydroxyC _1-6 alkyl, C _1-6 alkyloxycarbonylC _1-6 alkyl or C _3-6 alkenyl; R ¹ and R ² together with the nitrogen atom to which they are attached may form a pyrrolidinyl, morpholinyl or piperidinyl group; X represents N or CR ³ ; R ³ represents hydrogen or C _1-6 alkyl; R ⁴ represents phenyl or substituted phenyl; A is -C (= O)-, Or -CR ⁷ R ^8- , wherein R ⁵ and R ⁶ each independently represent hydrogen or C _1-4 alkyl, R ⁷ represents hydrogen or OH, R ⁸ is hydrogen or C _1-6 Alkyl; Substituted phenyl is 1, 2 or 3 independently selected from the group consisting of halo, hydroxy, C _1-6 alkyloxy, benzyloxy, C _1-6 alkylthio, trifluoromethyl, C _1-6 alkyl and cyano Phenyl substituted by 3 substituents. The compound of claim 1, wherein R ¹ is hydrogen, C _1-6 alkyl or C _3-6 alkenyl; R ² is C _1-6 alkyl, C _3-6 cycloalkylmethyl, hydroxyC _1-6 alkyl, C _3-6 alkenyl, C _1-6 alkyloxycarbonylC _1-6 alkyl, preferably R ² is C _2-4 alkyl, C _3-4 alkenyl, cyclopropylmethyl or hydroxyC _2-4 alkyl; R ¹ and R ² together with the nitrogen atom to which they are attached are capable of forming a pyrrolidinyl, morpholinyl or piperidinyl group. The compound of claim 2, wherein R is amino or C _1-4 alkyl; R ³ is hydrogen or C _1-4 alkyl; R ⁴ is phenyl substituted by 2 or 3 substituents selected from the group consisting of halo, C _1-4 alkyloxy and C _1-4 alkyl. The compound of claim 3, wherein R is C _1-2 alkyl; R ¹ is C _2-4 alkyl or C _3-4 alkenyl; R ² is C _2-4 alkyl, C _3-4 alkenyl, cyclopropylmethyl or hydroxyC _2-4 alkyl; R ³ is C _1-2 alkyl; R ⁴ is phenyl substituted by 2 or 3 substituents selected from the group consisting of methoxy and C _1-2 alkyl. The compound of claim 1, wherein X is CR ³ , wherein R ³ is C _1-2 alkyl, R is C _1-2 alkyl, R ¹ is C _2-4 alkyl, and R ² is cyclopropylmethyl , R ⁴ has 2,4,6-position C _1-2 alkyl or phenyl di- or trisubstituted by methoxy, wherein A is -CO- or -CH _2- . The compound of claim 5, wherein R ³ and R are methyl and R ¹ is n-propyl. A pharmaceutical composition comprising a compound according to any one of claims 1 to 6 and a pharmaceutically acceptable carrier or diluent. A compound according to any one of claims 1 to 6 for use as a medicament. A method for antagonizing the CRF receptor in warm blooded animals, characterized by administering an effective amount of the compound according to any one of claims 1 to 6 to warm blooded animals. A method for treating a disease caused by hypersecretion of CRF in a warm blooded animal, characterized by administering to the warm blooded animal an effective amount of the compound according to any one of claims 1 to 6. The method of claim 10, wherein the disease is selected from depression, anxiety-related disorders, food intake disorders, immune suppression by stress, stroke, Cushing's disease, infant cramps, epilepsy, seizures and inflammatory symptoms. The method of claim 11, wherein the disease is anorexia nervosa, bulimia or irritable bowel symptoms. A method for preparing a composition according to claim 7, characterized in that the active ingredient is thoroughly mixed with the carrier or diluent. a) reacting pyrimidine or triazine of general formula (II) with amine HNR ¹ R ² ; b) R ⁴ -Mg-halo and Grinard react with pyrimidine or triazine of general formula (III) to obtain a compound of general formula (Ia), and the obtained compound of (Ia) is Grignard reagent R ⁵ R ⁶ CH-Mg-halo is reacted to give a compound of formula (Ib), and then the obtained compound of formula (Ib) is dehydrated to convert to a compound of formula (Ic). Converting the compound of Ia) to a compound of Formula (Ib) or Formula (Ic); Reducing the compound of formula (Ia) to convert it to a compound of formula (Id); c) reacting a thiourea of formula (IV) with a compound of formula (V) to afford a compound of formula (I-e); d) reacting intermediate (VI) with Grignard reagent R ⁴ -Mg-halo to afford the compound of formula (If); e) reacting compound (Ia) with Grignard reagent R ⁸ -Mg-halo to afford the compound of formula (If); f) reducing compound (I-f) to compound (I-g); After the compound of formula (I) is interconverted by a functional group conversion reaction known in the art; A process for preparing a compound according to any one of claims 1 to 6, characterized in that optionally an acid-addition salt is prepared by treating the compound of formula (I) with a suitable acid: In the above scheme, Each substituent has the meaning defined in any one of claims 1 to 6, W represents a suitable leaving group, -Halo represents a halogen atom.